We have recently demonstarted that lncRNAs robustly regulate systemic lipid and glucose metaoblism and their dysregulation might contribute to the pathogenesis of metaboic disease in mice (Li et al, Cell Metabolism, 2015, Ruan et al, Cell Reports, 2016 and Yang et al, in press in Cell Metabolism, 2016). If lncRNAs play similar roles in humans, understanding their functions could provide important insights into human metabolic physiology and open up novel therapeutic strategies. However, lncRNAs are much less conserved among species and it is estimated that majority (81%) of human lncRNAs are either primate- or human-specific (Nature 2014 Jan 30; 505). Therefore information on lncRNA functions generated in rodents might not be directly applicable to human physiology and human-specific lncRNAs might carry out functions unique to human metabolism that can only be adequately studied in human cells or tissues. To overcome this limitation and to develop a system to study human lncRNAs in a pathophysiologically relevant setting, we have successfully produced liver-specific humanized mice in which over 90% mouse hepatocytes are replaced by engrafted human hepatocytes. To identify functionally important lncRNAs in human metabolism, we have performed several genomewide screens in the humanized mice and identified hundreds of human-specific lncRNAs implicated in metabolic regulation. We have further demonstrated that a number of selected lncRNAs are strongly regulated by glucose and lipid metabolites as well as key metabolic hormones in human primary hepatocytes. Furthermore, loss-of-function studies also confirmed that two lncRNAs robustly regulate gluconeogenesis and lipogenesis in hepatocytes respectively. We are currently investigating their physiological functions using the humanized mice and at the same time studying their mechanism of actions using RNA precipitation coupled with proteomics analysis and next generation sequencing.